P485: AZACITIDINE, VENETOCLAX AND GILTERITINIB FOR PATIENTS WITH NEWLY DIAGNOSED FLT3-MUTATED ACUTE MYELOID LEUKEMIA: A SUBGROUP ANALYSIS FROM A PHASE II STUDY
Authors: Nicholas Short, Walid Macaron, Courtney Dinardo, Naval Daver, Musa Yilmaz, Gautam Borthakur, Guillermo Montalban-Bravo, Guillermo Garcia-Manero, Ghayas Issa, Koji Sasaki, Jan Burger, Abhishek Maiti, Yesid Alvarado, Jennifer Thankachan, Regina Abramova, Lewis Nasr, Cedric Nasnas, Marianne Zoghbi, Tapan Kadia, Marina Konopleva, Hagop Kantarjian, Farhad Ravandi
Journal: HemaSphere (2023)

Background:FLT3 mutations are associated with a poor prognosis in newly diagnosed AML. Treatment with a hypomethylating agent (HMA) plus venetoclax is standard of care for older/unfit patients (pts) with newly diagnosed FLT3-mutated AML; however, relapse of the FLT3-mutated clone is common and historical 1-year overall survival (OS) is 40-60% (Konopleva MY et al. Clin Cancer Res 2022). To improve these outcomes, we designed a phase II study to evaluate the triplet regimen of azacitidine, venetoclax and gilteritinib (a potent oral FLT3 inhibitor) in pts with newly diagnosed FLT3-mutated AML. Aims: We evaluated the efficacy and safety of azacitidine, venetoclax and gilteritinib in pts with newly diagnosed FLT3-mutated AML. The primary endpoint was the CR/CRi rate of the regimen. Methods: In this phase II study, pts with newly diagnosed FLT3-mutated AML (either ITD or TKD) who were unsuitable for intensive chemotherapy were eligible. Pts were required to have a performance status ≤3, total bilirubin ≤2.5 x ULN, ALT/AST ≤3 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1, pts received azacitidine 75 mg/m2 SC/IV on days 1-7, venetoclax on days 1-28, and gilteritinib 80mg on days 1-28. Bone marrow was performed on day 14 and if blasts were <5% or the marrow was insufficient/aplastic, then both venetoclax and gilteritinib were held. For cycles 2 and beyond, azacitidine 75 mg/m2 SC/IV was given for 5 days, venetoclax was given for 7 days and gilteritinib was given continuously. Results: Between October 2020 and January 2023, 30 newly diagnosed pts were treated. Their baseline characteristics are shown in Table 1. The median age was 71 years (range, 18-86). One pt <60 years of age (age 18) was enrolled due to severe COVID-19 pneumonia at the time of AML diagnosis. 22 (73%) had a FLT3-ITD and 8 (27%) had a FLT3-TKD mutation. All pts responded, with 27 pts (90%) achieving CR and 2 pts (6%) achieving CRi (CR/CRi rate: 96%). One additional pt (4%) achieved MLFS as best response. On the day 14 bone marrow, 28 pts (96%) achieved either morphologic remission with <5% blasts (n=21) or had an insufficient/aplastic marrow (n=7). Twenty-six pts (87%) achieved flow MRD negativity and 27 pts (90%) cleared the FLT3 mutation using a PCR assay with sensitivity of 10-2. Twelve pts (40%) proceeded to allogeneic stem cell transplantation (alloSCT) in first remission, 4 (13%) relapsed, 1 (3%) died in CR, and 13 (43%) are in ongoing response without alloSCT. Among the 4 relapses, 1 pts was FLT3-positive at relapse, 2 were FLT3-negative, and 1 relapsed with extramedullary-only disease. Four pts have died (2 after relapse, 1 from post-HSCT complications, and 1 due to sepsis while in CR). With a median follow-up of 14.3 months, the estimated 1-year RFS is 78% and 1-year OS is 86% (Figure 1). In a landmark analysis, outcomes were similar regardless of whether or not alloSCT was performed (1-year OS 91% versus 90%, respectively). The 1-year OS for patients with a FLT3-ITD mutation or FLT3-TKD mutation were 80% and 100%, respectively, and 1-year OS for patients <75 years of age or ≥75 years of age were 81% and 100%, respectively. Summary/Conclusion: The combination of azacitidine, venetoclax and gilteritinib is safe and effective in pts with FLT3-mutated AML. The combination appears to improve response rates and OS compared to historical expectations of FLT3-mutated AML treated with HMA plus venetoclax without a FLT3 inhibitor.Keywords: flt3 inhibitor, Acute myeloid leukemia, FLT3, Clinical trial